Derivatives of 11alpha-hydroxy-11, 19-epoxyandrostanes



2,975,173 DERIVATIVES or 11a-HYDROXY-11,19-

. EPOXYANDROSTANES John S. Baran, Chicago, 111., assignor to G. D. Searle & Co., Chicago, 11]., a corporation of Delaware No Drawing. Filed Sept. 28, 1959, Ser. No. 842,565 8 Claims. (Cl. 260-23955) The present invention relates to novel derivatives of 1la-hydroxy-l1,19-epoxyandrostanes and, more particu-' larly, to the compounds of the general structural for mula on i L\:/\

V H wherein R is a member of the class consisting of hydrogen and lower alkyl radicals and A is a member of the class consisting of CO--CH OH, -CO-CH I, COCH and COOH radicals.

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Patented Mar. 14, 1961 pregnane-3,20-dion'es with alkali metal metaperiodates yields 3-oxo-11a hydroxy 11,19-epoxyandrostane-17[3 carboxylic acid which, on treatment with a lower alkanol of the formula ROH in the presence of a catalytic amount of such acidsas p-toluenesulfonic acids yields 3-oxo-llaalkoxy-11, l9- epoxyandrostane l7f3-carboxylic acids.

The compounds claimed are active pharmacological agents Thus, they inhibit the sodium retention produced by desoxycorticosterone. The invention will appear in further detail from a consideration of the examples presented herewith. However, the invention is not to be construed as limited in spirit or in scope by the details set forth herein. In these examples quantities are indicated in parts by weight. 7

Example 1 I parts of pyridine is prepared by adding the chromic The compounds of this invention are conveniently prepared from the corresponding 3-oxo-11a -alkoxy-11,19- epoxy-5a,14a-card-20(22)-enolides of the structural formula wherein R is a lower alkyl group. These =cardenolides are subjected to ozonolysis and then treated with zinc and an organic acid to yield an l1a-alkoxy-11,19-epoxyanhydride to the pyridine with stirring over a period of one hour at l520 C. To this mixture is added a slurry of 30 parts of ouabagenin-1,19-acetonide and 400 parts of pyridine. After the mixture has been stirred for one day, it is diluted with 1500 parts of chloroform and filtered. The filtrate is extracted with 500 parts of saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and taken to dryness under vacuum. The residue is dissolved in 1000 parts of ethanol and the solution is stirred at reflux for 1 hour with 290 parts of basic alumina. The mixture is filtered and the alumina is extracted with hot ethanol; the-combined filtrate and the mixture is diluted with, methanol until the product which precipitates partially during the hydrogenation is] 1 dissolved. The mixture is then filtered and thesfiltrate' is concentrated under vacuum at 25 C. to a small volwire. The resulting solid is collected on a filter, washed with methanol and dried. Crystallization from:acetone'- methanol yields 3-oxo-5B,11a,14;8 trihydroxy 11,19

, epoxy-card-20(22)-enolide which melts at about 178:-

" 181 C. Infrared maxima are observed at 2.82, 2.90,

2l-hydroxypregnane-3,20-dione of the structural formula cient of about 17,300. The compound isin equilibrium; with 3,11-dioxo-5fi,14fi,19-trihydroxycard-20(22) enolide.

The compounds thus in equilibrium have thestructural Treatment of 11a alkoxy-l1,19repoxy;215hydroxy:

3.38, 5.69-5.77, 5.86, 6.l3, 8.61, 9.73, 10.30, and 11 .07 microns. A methanolic'solution shows anultraviolet maximum at 218 millimicrons with an extinction coefiia formulas CH3 s/\i no 1 H10 o- H H p A mixture of 2 parts of 3-oxo-5/3,11a,14p-trihydroxy-l;

o 11,19-epoxycard-20(22)-enolide and l0parts ,offiacetic; acid is refluxed for 10 minutes and then evaporatedto T dryness under vacuum. .The residue: is trituratpd'avith acetone and petroleum ether to yield a crystalline product. This is collected by filtration, washed with acetone and dried. Crystallization of the crude product from acetone yields 3-oxo-ll 14fl dihydroxy 11,19-epoxycarda-4,20(22)-dienol ide melting at about 248250 C. Infrared maxima are observed at 2.89, 3.38, 5.71, 5.83, 6.02, 6.16, 8.70, 9.71, 11.30, 11.56, and 12,30 microns. A methanolic solution shows ultraviolet maxima at 218 and 244 mill-imicrons with extinction coeflicients of about 20,000 and 14,300, respectively.

A solution of 6 parts of 3-0X0-110:,14/3-dihYd1'OXY-11, 19-epoxycarda 4,20(22) dienolide, 60 parts of metl 1 anol and 0.5 part of p-toluenesulfonic acid is stirred for several hours and then concentrated to a small volume. The solid which precipitates is collected by filtration, washed with methanol, and dried. Crystallization from ethanol yields 3-oxo 1lu-rnethoxy-l1,19-epoxy-14fl-hydroxy-carda-4,20(22)-dienolide which melts at about 258-261 C. Infrared maxima are observed at 2.82, 3.40, 5.77, 6.02, 6.18, 7.69, 8.37, 9.09, 10.36, and 11.64 microns. A methanolic solution shows ultraviolet maxima at 219 and 240 millirnicrons with extinction coefficients of about 22,000 and 17,500, respectively. The specific rotation of a 1% chloroform solution ca is +149.s.

Substitution of 70 parts of ethanol for the methanol used in the precedingprocess yields 3-oxo-11a-ethoxy-11, 19-epoxy-14fi-hydroxycarda-4,20(22) dienolide. Ultraviolet maxima are shown by a methanolic solution at about 219 and 240 millimicrons with molecular extinction coefficients of about 21,800 and 17,300, respectively.

Example 2 To a mixture of 20 parts of 3-oxo-11a-methoxy-11,19- epoxy 14;? hydroxycarda 4,20( 22) dienolide and 100 parts of pyridine is added a solution of 6.4 parts of thionyl chloride in 25 parts of pyridine at C. After minutes the solution is diluted with 350 parts of chloroform. The organic solution is washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated to dryness under vacuum. Crystallization of the crude product from dichloromethane yields 3-oxo-l la-methoxy-l 1, 19-epoxycarda-4,14,20 (22 trienolide melting at about 212214 C. Infrared maxima are observed at 3.44, 5.72, 6.05, 6.14, 6.22, 9.30, 9.51, 10.05, 11.62, and 12.50 microns. A methanolic solution shows ultraviolet maxima at 217 and 241 millimicrons with molecular extinction coefficients of about 20,200 and 18,500, respectively. The specific rotation of a 1% chloroform solution is +119.5.

Substituting as a starting material 3-oxo-11a-ethoxy-11, 19-epoxy-14/3-hydroxycarda-4,20(22)-dienolide there is obtained 3-oxo-11a-ethoxy 11,19 epoxycarda 4,14,20 (22)-trien0lide. The ultraviolet absorption spectrum shows maxima at 217 and 241 millimicrons with molecular extinction coefficients of about 20,000 and 18,500, respectively.

Example 3 A mixture of 4 parts of 3-oxo-11a-methoxy-1L19- epoxycarda-4,14,20(22)-trienolide, 40 parts of ethyl acetate, 40 parts of methanol and 1 part of 5% palladiumon-charcoal is stirred in an atmosphere of hydrogen until two equivalents have been absorbed. The mixture is filtered and the filtrate is concentrated to a small volume. The residue which precipitates is collected by filtration, Washed with methanol and dried. Crystallization of the crude product from dichloromethane in methanol yields 3-oxo-11a-methoxy-11,19-epoxy 50,l4ot card (22)- enolide which melts at about 192-194 when heated rapidly. When heated slowly it appears to soften at about 190 C. and then melts at about 230250 C. Infrared maxima are observed at 3.40, 5.70, 5.83, 6.15, 8.70, 9.88, 11.20 and 11.50 microns. A methanolic solution shows an ultraviolet maximum at 217 millimi crons with an extinction coeflicient of about 15,000.

The specific rotation of a 1% chloroform solution is +1265. The compound has the structural formula 1 CH3 CH:

Example 4 A solution of 1 part of 3-oxo-l1a-methoxy-1L19- epoxy-5u,14a-card-20(22)-eno1ide, parts of dichloromethane and 100 parts of ethyl acetate is saturated with ozone for 3 hours at -60". The solution is then stirred with 1 part of zinc and 5 parts of acetic acid for 5 minutes. The mixture is diluted with dichioromethane and filtered. The filtrate is washed with aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness under vacuum. The residue is dissolved in 50 parts of methanol and mixed with a solution of 0.5 part of potassium bicarbonate in 30 parts of water. The mixture is stirred for 16 hours and then extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness. The residue is triturated with acetone and ether to yield crude llamethoxy 11,19 epoxy-21-hydroxy-5e-pregnane 3,20- dione which upon recrystallization from acetone melts at about 178-180 C. Infrared maxima are observed at 2.96, 3.39, 5.83, 9.13, 9.95, 10.18, 10.90, 11.50, 13.18 microns. The specific rotation of the chloroform solution [01], is +134.5. The compound has the structural formula CHzOH Substituting as the starting material 3 oxo 11aethoxy-l1,19-epoxy-5a,14a-card-20(22)-eno1ide there is obtained 11a-ethoxy-11,19-epoxy 21 hydroxy-Sa-pregnane-3,20-dione. Infrared maxima are observed at 2.96, 3.4 and 5.83 microns.

Example 5 To a solution of 2 parts of 11a-methoxy-1l,19-epoxy- 21-hydroxy-5a-pregnane-3,20-dione in 50 parts of acetone and 20 parts of water is added 0.1 part of p-toluencsulfonic acid. The solution is concentrated to a small volume at room temperature and a crystalline precipitate forms which is collected by filtration, washed and dried. Recrystallized from acetone and petroleum ether, the lla-hydroxy-1Ll9-epoxy 21 hydroxy-5a-pregnane- 3,20-dione melts at about -167 C. Infrared maxima are observed at about 2.88, 3.39, 5.83, 9.90, 10.74 and 11.18 microns. The specific rotation of the chloroform solution [aj is +107 Example 6 A mixture of 1.9 parts of 11a-methoxy-11,19-epoxy- 21-hydroxy-5a-pregnane-3,20-dione, 10 parts of anhydrous pyridine and 2.1 parts of p-toluenesulfonyl chloride is permitted to stand at C. for 18 hours. To the mixture are then added over a period of minutes parts of ice and 100 parts of water. The mixture is diluted with dichloromethane, washed successively with water, dilute aqueous hydrochloric acid, water, and aqueous sodium bicarbonate, dried over sodium sulfate and evaporated to dryness under vacuum. The residue, which contains the Ila-methoxy-l1,19-epoxy-21-(p-toluenesulfonyloxy)-5a-pregnane-3,20-dione is warmed with a solution of 2 parts of sodium iodide and 60 parts of acetone for 10 minutes. The mixture is evaporated to dryness and the residue is extracted with dichloromethane. This extract is filtered and the filtrate is taken to dryness. The residue, which contains the 11a-methoxy-11,l9- epoxy-21-iodo-5a-pregnane-3,20-dione, is stirred for 5 minutes with a mixture of 2 parts of zinc and 10 parts of acetic acid. The mixture is then diluted with dichloromethane and filtered. The filtrate is washed with water, saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated to dryness under vacuum. The residue, when triturated withmethanol, yields crude 1 lu-methoxy-l 1,19-epoxy-5a-pregnane-3,20-dione which, when recrystallized from methanol, melts at about 147- 148". Infrared maxima are observed at about 3.40, 5.84, 8.78, 9.42, 9.70, 10.20 and 11.58 microns. The specific rotation of the chloroform solution [001D is +133.4.

Substitution as a starting material of an equivalent amount of 2 parts of 11a-ethoxy-11,19-epoxy-21-hydroxy- 5a-pregnane-3,20-dione yields lla-ethoxy-l1,19-epoxy-5apregnane-3,20-dione. The compound shows infrared maxima at about 3.4 and 5.83 microns.

Example 7 Example 8 A solution of 1 part of 11a-methoxy-1L19-epoxy- 21-hydroxy-5a-pregnane-3,20-dione, 6 parts of sodium metaperiodate, 60 parts of acetone and 10 parts of water is permitted to stand for 1 day at room temperature. The mixture is then diluted with 60 parts of water and concentrated by evaporation of the acetone at room temperature under vacuum. The resulting precipitate is collected on a filter, washed with water and dried. On crystallization from acetone and petroleum ether 3-oxo- 11oz hydroxy 11,19 epoxy 5a androstane 175- carboxylic acid melts at about 195-196" C. Infrared The compound has the structural formula Example 9 A solution of 4 parts of 3-oxo-11a-hydroxy-1L19- epoxy-5a-androstane-l7 8-carboxylic acid in parts of methanol and 0.5 part of p-toluenesulfonic acid is permitted to stand for 2 hours after which it is taken to dryness and the residue is triturated with acetone and petroleum ether. The crude crystalline product is recrystallized from methanol to yield 3-oxo-11a-methoxy-l1, 19-epoxy-5a-androstane-17,8-carboxylic acid which shows infrared maxima at about 3.4, 5.85, and 5.9 microns.

Substitution of 100 parts of ethanol in the procedure of the foregoing example yields 3-oxo-11a-ethoxy-11,19- epoXy-Sa-androstaneF17fi-carboxylic acid which shows maxima at about 3.4, 5.84, and 5.9 microns.

What is claimed is:

1. A compound of the structural formula wherein R is a member of the class consisting of hydrogen and lower alkyl radicals and X is a member of the L CH3 R (300B wherein R is a member of the class consisting of hydrogen and lower alkyl radicals.

7. 3 oxo -11oc hydroxy -11,19 epoxy 5a. an

drostane-17fi-carboxylic acid.

8. 3 oxo 11a methoxy 11,19 epoxy 5d androstane-flfi-carboxylic acid.

References Cited in the file of this patent Baumgartner et al.: Experientia, vol. XIII, No. 5,

maxima are observed at 2.86, 2.96, 3.38, 5.81, 5.88, 76 May 15, 1957, pages -7. 

1. A COMPOUND OF THE STRUCTURAL FORMULA 